Monoclonal antibody (mAb) for the treatment of cancer, like AVASTIN™ (anti-VEGF) for colon cancer, RITUXAN™ (Rituximab; anti-CD20) for Non-Hodgkin's Lymphoma and HERCEPTIN™ (anti-Her2) for breast cancer have demonstrated that unconjugated antibodies can improve patient survival without the toxicity experienced with conventional chemotherapy treatments.
Monoclonal antibodies bind to target cells and activate the immune system to eliminate the cell. Increased efficiency can be achieved by conjugating a therapeutic agent to mAbs to form an antibody drug conjugate (ADC). ADCs deliver the therapeutic agent directly to the cell without the need for activating the immune response system. The linkage of the antibody to the drug can be direct, or indirect via a linker. One of components believed to be important for developing effective and well-tolerated ADCs is the composition and stability of the linker. For some types of ADCs, the linker desirably provides serum stability, yet selectively releases the drug at or within the target cell.
Attachment of a linker to a mAb can be accomplished in a variety of ways, such as through surface lysines, reductive-coupling to oxidized carbohydrates, and through cysteine residues liberated by reducing interchain disulfide linkages. A variety of ADC linkage systems have been described in the literature, including hydrazone-, disulfide- and peptide-based linkages. Some hydrazone and disulfide-based linkers can be labile in circulation, resulting in release of drug outside the targeted tissue. It is believed that this premature release of drug might lead to systemic toxicity or organ-specific toxicity and/or less than optimal therapeutic efficacy. Peptide-based linker strategies may provide linkers of higher stability; however, the increased associated hydrophobicity of some linkers may lead to aggregation, particularly with strongly hydrophobic drugs. Such aggregation may lead to non-specific uptake of the ADCs into non-targeted tissues, potentially affecting non-target toxicity.
Consequently, there remains a need for targeted delivery of drugs, resulting in reduction or elimination of targeted cells while reducing toxicity to non-target cells.
These and other limitations and problems of the past are solved by the present invention. The recitation of any reference in this application is not an admission that the reference is prior art to this application.